1. Field of the Invention
The present invention relates to a method for forming and collecting fine particles of a substance, such as a pharmaceutical or biological substance, by anti-solvent precipitation, particularly but not exclusively suitable for administration to organisms. The invention also relates to fine particles of biological substances produced by the method and to compositions, particularly pharmaceutical compositions, containing an active substance.
2. Background Information
Throughout this specification, unless stated otherwise, where a document, act or item of knowledge is referred to or discussed, this reference or discussion is not an admission that the document, act or item of knowledge, or any combination thereof, at the priority date, was part of the common general knowledge.
Production of uniform micron size particles (or within a narrow size range) of fragile molecules such as proteins is a challenge in the pharmaceutical industry. One use of fine particles is pulmonary absorption of drugs. This is an important route of entry for many indications including some pulmonary diseases, for example, bronchial asthma. One advantage of this mode of administration is that access to the circulation is rapid, because the surface area is large. As well as almost instantaneous absorption of the drug into the blood, delivery to the lung has the advantages of avoidance of hepatic first-pass loss, and in the case of pulmonary disease, local application at the desired site of action.
Delivery to the lung may also provide an alternative for the treatment of conditions that have traditionally been treated by systemic administration of a drug. The administration of proteins is a case in point. Insulin is currently administered by injection because it is not stable in the gastrointestinal tract. Diabetic patients need to self-administer several injections. However, there is a lack of compliance with the use of injections because of the associated inconvenience and pain. Administration of the protein to the lung is more likely to be accepted by such patients and is therefore an attractive alternative to injections, as long as the protein can be formed as fine particles, without significant loss of biological activity. Usual criteria for the use of aerosol delivery for the administration of therapeutic drugs to the lung are that the drug is in particulate form with the particles having a size in the range of about 0.05-10 μm, preferably 1-5 μm while (obviously) retaining biological activity, which often requires the substance's structure to be maintained. A common problem in manufacture of such particles is unacceptable variation in particle size.
Drugs in the form of fine particles are also suitable for use in the area of oral, controlled or sustained release delivery. One application of such technology is in the case of a drug in which there is a small difference in dosage levels between the drug being effective and being toxic. In the latter technology, it is also important that the particles have a uniform particle size.
Another application of fine particles of pharmaceuticals is transdermal drug delivery. Apart from traditional sub-cutaneous, intravenous, etc. injection, new methods of administration are being used, such as lasers to create a fine channel through the skin for drug delivery. A similar mechanism involving high-pressure drug delivery transdermally is also being used. Thus, the applications for fine or micron-sized pharmaceutical particles are increasing.
Dense gas techniques utilizing fluids, near or above their critical point, as a solvent or anti-solvent have been developed in recent years. Two dense gas methods have been considered for the production of solid particles. The first method is known as the Rapid Expansion of Supercritical Solutions (RESS), and involves expanding a supercritical solution of the material of interest through a nozzle. Whilst providing an effective method for producing some fine particles, the applicability of the RESS method is limited by the low solubility of proteins in dense carbon dioxide.
The second method, known as the gas anti-solvent process, involves rapidly precipitating solutes from organic solutions, typically using dense carbon dioxide as an anti-solvent. The anti-solvent expands the solution, thereby decreasing the solvation power of the solvent, and eventually resulting in the precipitation of the solute.
Gas anti-solvent processes have been utilized for the generation of micron-sized particles in two modes. The first mode, known simply as the gas anti-solvent process (GAS), involves the gradual addition of an anti-solvent to the organic solution containing the solute until the precipitation occurs. The second mode, known as the Aerosol Solvent Extraction System (ASES), involves continuous introduction of a solution containing the solute of interest through a nozzle into a flowing dense gas stream. As the solution is sprayed in to the dense gas, high degrees of supersaturation result in the precipitation of fine particles. In general, precipitation using this process is rapid and requires mild operating temperatures and pressures.
The GAS process has been attempted for the generation of micron-sized particles of insulin, lysozyme, and peroxidase. The difficulty of applying these techniques to the production of micronised particles of pH sensitive proteins is that they involve exposure of the protein to organic solvents, the latter being potential denaturants. This would, for example, inactivate insulin. Organic solvents are also undesirable as they are more difficult to dispose of. Thus, this process is largely unsuitable.
In one attempt to overcome this limitation, a form of the ASES process has been developed, referred to as Solution Enhanced Dispersion by Supercritical Fluid (SEDS). SEDS involves using the ASES process but with a special coaxial nozzle which, in part, overcomes the problem of exposure to organic solvents.
Current apparatus utilising these processes, particularly ASES, for the production and collection of particulate products comprise a precipitator and a collection device in the same chamber. The solution containing the product of interest and the anti-solvent (which contains the dense gas and, optionally, a modifier) are passed through the precipitation chamber co-currently. As the particles are formed, they fall to the bottom of the collection device under gravity and can become compacted, aggregated (physical association) or agglomerated (chemically bonded). The particles can also become further compacted during the washing stage at the end of the process, due, for example, to the high pressure and high flow-rate of the dense gas anti-solvent.
Aggregation occurs when a collection of two or more particles are held together by weak cohesive forces, such as van der Waal's forces. Aggregates can be dispersed with shear forces and/or solvents. Agglomeration on the other hand, occurs when a collection of two or more particles are held together by strong inter-particle forces such as crystal bonds. Agglomerates are more difficult to break up and disperse.
In small particle formation processes, it is desirable to avoid the particles becoming agglomerated or compacted, since it is more difficult to break this material up, particularly while avoiding damage to the active component. The particles resulting from such processes are, therefore, not uniform in size and shape, which is not ideal for the use of such particles in pharmaceutical applications. However, some degree of aggregation may be desirable in some situations where the particles produced are too fine to be collected. The fine powders that have not become aggregated may be washed out of the system, resulting in a low yield. Aggregation between particles makes the particles larger and easier to collect, and after collection the aggregate can be broken up by mechanical force.
Particles to be used for the pulmonary delivery of pharmaceuticals should ideally be less than 5 to 10 μm in diameter. Particles of this size are more easy to aerosolise, and when inhaled, these particles are easily able to reach the lungs. However, when particles become compacted in the collection chamber, the mass fraction of particles with a diameter of less than 5 μm (and thus suitable for pulmonary delivery) is low.
Collection processes using known single-stage apparatus are essentially batch processes with short run times, due to the necessity of regularly stopping the run to remove the precipitated particles before caking (i.e., aggregation of a mass of fine particles which may form a block to a chamber's outlet) occurs. The production of particles using such apparatus is thus, necessarily, a batch-wise process. The process is therefore inefficient and there can be poor yields and recovery of the product.
The invention is directed towards an apparatus for particle formation which operates in a more efficient manner (i.e., increase the yield of fine particles collected relative to starting materials) and does not damage the particles that are formed using the apparatus or substantially increase the average particle size collected.